Exploring the Causal Link Between Autoimmune Diseases and Pulmonary Arterial Hypertension: A Bidirectional Mendelian Randomization Study.

Background: Pulmonary arterial hypertension (PAH) is a severe vascular disorder with a multifactorial etiology, including potential genetic predispositions. Understanding the causal relationship between autoimmune diseases and the risk of developing PAH can inform clinical strategies for prevention and treatment.

Methods: We conducted a two-sample Mendelian Randomization (MR) analysis to evaluate the causal effect of genetic predisposition to five autoimmune diseases (systemic lupus erythematosus [SLE], rheumatoid arthritis [RA], inflammatory bowel disease [IBD], multiple sclerosis [MS], and type 1 diabetes [T1D]) on the risk of PAH. This involved employing various MR methods (IVW, MR-Egger, Weighted median, Simple mode, and Weighted mode), as well as conducting tests for heterogeneity and horizontal pleiotropy.

Results: The analysis revealed a significant association between genetic predisposition to RA and IBD with an increased risk of PAH (RA: OR = 1.28, 95% CI [1.01-1.61], p = 0.042; IBD: OR = 1.29, 95% CI [1.01-1.64], p = 0.043). However, no association was observed between genetically determined MS, SLE, and T1D with the risk of PAH (MS: p = 0.876; SLE: p = 0.564; T1D: p = 0.061). Additionally, tests for heterogeneity and pleiotropy provided no evidence of their influence, suggesting the robustness of these associations. Reverse MR analysis also indicated no significant effect of PAH on the genetic susceptibility to these autoimmune diseases.

Conclusion: The findings suggest a possible genetic causative link between RA and IBD and the risk of developing PAH. Conversely, genetic predisposition to MS, SLE, and T1D does not appear to influence PAH risk. Understanding these relationships may offer insights into the pathophysiology of PAH and inform screening strategies within at-risk populations.